Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS). While the genetic and environmental factors that trigger MS vary, the common pathological outcome of the disease is the destruction of myelin-producing oligodendrocytes and their associated neuronal axons through a process called encephalomyelitis. Development of encephalomyelitis requires coordinated expression of a large number of genes that mediate the activation, migration and effector function of inflammatory cells (activated lymphoid and myeloid cells). These include genes that encode inflammatory cytokines, chemokines, and cytotoxic enzymes. Expression of these inflammatory genes is tightly regulated at the transcriptional level by specific transcription factors. Recent studies indicate that, c-Rel, the lymphoid member of the Rel/nuclear factor-κB (Rel/NF-κB) family, is a long sought-after transcriptional regulator of EAE. The mammalian Rel/NF-κB family consists of five members, each of which is endowed with a distinct set of function not shared by other members, although each member may also perform additional functions common to the family.
Thus, unlike other members that are ubiquitously expressed, c-Rel is preferentially expressed by inflammatory cells, and is involved in regulating a special subset of immune responses. c-Rel-deficient mice do not suffer from developmental problems or infectious diseases, but are resistant to inflammatory diseases (despite the normal expression of other Rel/NF-κ B proteins); c-Rel-deficient T cells are competent in survival and Th2 type responses but are severely compromised in their Th1 and Th17 type responses.
The Rel/NF-κB family of transcription factors represents one of the most attractive targets for anti-inflammatory therapy. Because Rel/NF-κB directly controls the expression of multiple inflammatory genes, its blockade is more effective for controlling inflammation than blocking one or a few downstream inflammatory genes or proteins. The first generation Rel/NF-κB drugs that block the entire Rel/NF-κB family have already been tested in both humans and animals. These include proteasome inhibitors (e.g., the FDA-approved PS-341), Rel/NF-κB decoy oligodeoxynucleotides and the NBD (nemo-binding domain) peptides, which are highly effective in preventing and treating models of autoimmune diseases including EAE. Additionally, glucocorticoids, which are currently used to control acute inflammation in MS patients, mediate their immunosuppressive effects, at least in part, through inhibiting Rel/NF-κB (glucocorticoids upregulate IKB expression and bind directly to Rel/NF-κB). However, because most Rel/NF-κB proteins are ubiquitously expressed and are involved in a variety of biological processes not related to autoimmunity, these drugs have significant side effects. Therefore, they can only be used for a short period of time to control acute inflammation.